**5. Carotid artery stenting**

Along with CEA, carotid artery stenting (CAS) has emerged as an alternative treatment strategy for patients with carotid artery disease. Initially proponents of angioplasty and stenting projected that this procedure could overcome the risks associated with CEA and provide a minimally invasive alternative for patients. However at this time the utility of CAS is highly debated with CEA remaining the standard of care in most asymptomatic and symptomatic patients.

There have been very few studies that have specifically addressed CAS in asymptomatic patients and most of the data available comes from high-risk registries which include patients with lesions located at or above the level of C2, contralateral carotid occlusion, severe ulcera‐ tion and tandem intracranial stenosis, age over 80, active coronary artery disease or congestive heart failure, and patient's with "hostile necks" (immobile neck, previous irradiation, previous surgery on the ipsilateral side or previous surgery on the contralateral side with vocal cord paralysis). In the SAPPHIRE trial, which population included 70% asymptomatic high-risk patients, their results found cumulative perioperative incidence of death, stroke, and MI of 5.4% for CAS and 10.2% for CEA. [61] Their results found that CAS with cerebral protection was not inferior to CEA. This study, however had several limitations including failure to randomize >50% of patients, unaccounted for elevated incidence of perioperative stroke, and possible reporting bias. The Carotid Revascularization Endarterectomy versus Stent Trial (CREST) enrolled more than 1000 asymptomatic patients. Stroke and death rates after CAS were 2.6% and 1.1% respectively with a difference between CAS and CEA in asymptomatic patients for any periprocedural stroke being 2.5% versus 1.4%. [62-64] These results did not show significant difference between CAS and CEA. The results from this study, however, were based on procedures performed by highly experienced operators and have not been replicated by other trials. [65]

randomized to either medical management with aspirin or surgery. At 3 years, the risk of stroke was found to be 26.5% in the medical group compared to 7% in the surgery group with an absolute reduction of 14.9%. The actual incidence of ipsilateral stroke was 2.8% in the surgery group versus 16.8% in the medical group. [55] ECST trial also evaluated gender, age, severity of stenosis, plaque morphology, and time since last event. They found that risk of events increased with age and with male gender. They did not find any benefit for surgery over medical treatment in the mild stenosis group (10%-29%) unlike the severe stenosis group,

Based on these randomized studies there seems to be a consensus on which patients would benefit from operative intervention after an ischemic event, however the timing of interven‐ tion has been much debated. The risk ofrecurrent stroke after TIA or minor stroke is the highest within the first 7-10 days. According to a meta-analysis by Giles et al the risk of stroke after TIA is 6.7% at 48 hours and 10% at 7 days with more than half of the strokes occurring within the first 7 days doing so within the first 24 hours after the inciting event. [57,58] In another study by Ois et al. the rate of recurrent stroke in symptomatic patients with greater then 50% stenosis was determined to be 20.9% in the first 72 hours, 6.7% between 72 hours and 7 days and 3.7% between7 and14days.[59]These results support early interventioninthe first 48hours because the risk of recurrent stroke appears to outweigh the operative risk in patients who are medical‐ ly stable and have relatively small or no infarcts on imaging studies. Alternatively, for a completed stroke researchers advocate delayed surgical intervention for at least 4-6 weeks due to the risk of converting an ischemic cerebral infarction into a hemorrhagic one. Giordano et al reported on 49 CEAs done after a completed acute stroke. 27 of these were performed within 5 weeks of the event and 22 were done between 5 and 20 weeks. The early intervention group had a morbidity and mortality of 18.5% compared to nothing for the later group. [60] These

results seem to corroborate with observations in both the NASCET and ECST trials.

Along with CEA, carotid artery stenting (CAS) has emerged as an alternative treatment strategy for patients with carotid artery disease. Initially proponents of angioplasty and stenting projected that this procedure could overcome the risks associated with CEA and provide a minimally invasive alternative for patients. However at this time the utility of CAS is highly debated with CEA remaining the standard of care in most asymptomatic and

There have been very few studies that have specifically addressed CAS in asymptomatic patients and most of the data available comes from high-risk registries which include patients with lesions located at or above the level of C2, contralateral carotid occlusion, severe ulcera‐ tion and tandem intracranial stenosis, age over 80, active coronary artery disease or congestive heart failure, and patient's with "hostile necks" (immobile neck, previous irradiation, previous surgery on the ipsilateral side or previous surgery on the contralateral side with vocal cord paralysis). In the SAPPHIRE trial, which population included 70% asymptomatic high-risk patients, their results found cumulative perioperative incidence of death, stroke, and MI of

**5. Carotid artery stenting**

symptomatic patients.

which showed a 6-fold reduction in subsequent strokes over 3 years. [56]

8 Carotid Artery Disease - From Bench to Bedside and Beyond

**Figure 3.** 70 year old Male with a history of squamous cell carcinoma status post neck radiation and hemiglossectomy found to have a 90% asymptomatic left common carotid artery stenosis. A: Angiogram of left common carotid artery stenosis (arrow) B. Angiogrom showing cerebral protection device located in the left internal carotid artery (dashed arrow) and stent placed in common carotid artery stenosis (black arrow). C. Post stent placement angioplasty balloon inflated (arrow) D. Completion angiogram showing minimal residual stenosis after stent placed.

For symptomatic patients several major randomized trials comparing CEA versus CAS have been completed. These include the International Carotid stenting Study (ICSS), the Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy (SPACE) trial, the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3s) trial, the Stenting and Angioplasty with Protection in Patients at high risk for Endarterectomy (SAPPHIRE) trial and the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREAST).

**Trial Methods Results Conclusions**

and /or MI

[68,69] Nevertheless, all three of these trials strongly favor CEA over CAS.

The SAPPHIRE trial previously mentioned was another one of the initial trials comparing CAS versus CEA. This corporate sponsored study had a high proportion of patients who were asymptomatic and at high risk for CEA. Results at one year found primary end-points of ipsilateral stroke or death to be lower in the stenting group than in the CEA group (12.2% versus 20.1%; P=0.5) supporting the superiority of CAS over CEA. The clinical correlation to symptomatic patients however is unclear. The CREST trial, alternatively, was a randomized, prospective, multicenter trial, which included 2502 patients. This trial had about an equal



The ICSS was a randomized prospective, multicenter trial in 2010 composed of 1713 subjects with recently symptomatic carotid artery stenosis greater than 50% who were randomized to either CEA or CAS. At this time the 120-day reported results show that the CAS group had a stroke, death, and MI rates of 7.7%, 2.3% and 8.5%, respectively. These were significantly higher than rates in the CEA group, which were 4.1%, 0.8%, and 5.2% respectively. Also there was an additional group that was analyzed by MRI. This analysis showed a greater number of patients in the CAS group that had a new ischemic brain lesion compared to the surgery counterpart. [66] The EVA-3S and SPACE trial had similar protocols as the ICSS trial. EVA-3S study divided 259 patients to CAS with cerebral protection devices (CPD) and CEA. This study found a significant, 2.5, higher risk for 30-day stroke and death in the CAS group than in the CEA group (9.6% versus 3.9%). At 4 year follow-up the risk of periprocedural stroke or death, and nonperiprocedural ipsilateral stroke was also higher in the CAS group (11.1% versus 6.2%). [67] This trial however was limited by operator experience were physicians were only required to perform a minimum of two procedures with any device to qualify for enrollment. In the SPACE trial, which was larger with 1196 patients, the rate of death or ipsilateral ischemic stroke was 6.9% in the CAS group and 6.5% in the CEA group. At the end of two years results showed a greater probability of recurrent carotid stenosis of more than 70% in the CAS group Similar concerns were raised against the SPACE trial concerning the inexperience of the operators. The inconsistent use of CPDs was another concern raised by opponents of this trial.

SAPPHIRE Multicenter RCT comparing CAS vs. CEA in both symptomatic and asymptomatic patients -334 patients randomized ->70% of patients asymptomatic


6.4% CAS vs. 4.7% CEA on symptomatic status


http://dx.doi.org/10.5772/57258

11

Evaluation and Treatment of Carotid Artery Stenosis

lower in CEA in symptomatic




death

CEA Limitations:

randomized

compared to other trials



For symptomatic patients several major randomized trials comparing CEA versus CAS have been completed. These include the International Carotid stenting Study (ICSS), the Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy (SPACE) trial, the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3s) trial, the Stenting and Angioplasty with Protection in Patients at high risk for Endarterectomy (SAPPHIRE) trial and the Carotid Revascularization Endarterectomy

**Trial Methods Results Conclusions**







0.7% CAS vs. 0.3% CE

4.1% CAS vs. 2.3% CEA

1.1% CAS vs. 2.3% CEA - Combined endpoints: 7.2% CAS vs. 6.8% CEA -4 year follow up combined

and CEA




endpoints:


and/or Death

Stroke: 7.7% CAS vs 4.1% CEA Death: 2.3% CAS vs. 0.8% CEA MI: 8.5% CAS vs. 5.2% CEA










cause death

vs. CEA

group

group

similar


endpoint based


alternative to CEA \*CPD were optional

Versus Stenting Trial (CREAST).

symptomatic stenosis >50%

10 Carotid Artery Disease - From Bench to Bedside and Beyond


patients with symptomatic stenosis randomly assigned 180 days after TIA or stroke

ipsilateral stroke or death at

259 patients with severe symptomatic stenosis >60%



vs. CEA in both symptomatic and asymptomatic patients -2502 enrolled; 47% asymptomatic

ICSS 1713 patient with

CEA vs CEA

SPACE European study 1196

30 days

EVA-3S French multicenter study

CAS vs. CEA

death at 30 days

CREST RCT largest comparing CAS

to CAS vs. CEA -Primary endpoint: The ICSS was a randomized prospective, multicenter trial in 2010 composed of 1713 subjects with recently symptomatic carotid artery stenosis greater than 50% who were randomized to either CEA or CAS. At this time the 120-day reported results show that the CAS group had a stroke, death, and MI rates of 7.7%, 2.3% and 8.5%, respectively. These were significantly higher than rates in the CEA group, which were 4.1%, 0.8%, and 5.2% respectively. Also there was an additional group that was analyzed by MRI. This analysis showed a greater number of patients in the CAS group that had a new ischemic brain lesion compared to the surgery counterpart. [66] The EVA-3S and SPACE trial had similar protocols as the ICSS trial. EVA-3S study divided 259 patients to CAS with cerebral protection devices (CPD) and CEA. This study found a significant, 2.5, higher risk for 30-day stroke and death in the CAS group than in the CEA group (9.6% versus 3.9%). At 4 year follow-up the risk of periprocedural stroke or death, and nonperiprocedural ipsilateral stroke was also higher in the CAS group (11.1% versus 6.2%). [67] This trial however was limited by operator experience were physicians were only required to perform a minimum of two procedures with any device to qualify for enrollment. In the SPACE trial, which was larger with 1196 patients, the rate of death or ipsilateral ischemic stroke was 6.9% in the CAS group and 6.5% in the CEA group. At the end of two years results showed a greater probability of recurrent carotid stenosis of more than 70% in the CAS group Similar concerns were raised against the SPACE trial concerning the inexperience of the operators. The inconsistent use of CPDs was another concern raised by opponents of this trial. [68,69] Nevertheless, all three of these trials strongly favor CEA over CAS.

The SAPPHIRE trial previously mentioned was another one of the initial trials comparing CAS versus CEA. This corporate sponsored study had a high proportion of patients who were asymptomatic and at high risk for CEA. Results at one year found primary end-points of ipsilateral stroke or death to be lower in the stenting group than in the CEA group (12.2% versus 20.1%; P=0.5) supporting the superiority of CAS over CEA. The clinical correlation to symptomatic patients however is unclear. The CREST trial, alternatively, was a randomized, prospective, multicenter trial, which included 2502 patients. This trial had about an equal inclusion of symptomatic and asymptomatic patients. The primary endpoint of any stroke, MI or death at 30-days were similar between CAS and CEA (6.8% versus 7.2%). Upon further examination, patients in the CAS group had a lower rate of MI within 30 days (1.1% versus 2.3%) and patients in the CEA group had a lower 30-day rate of stroke (2.3% versus 4.1%). At one-year follow up quality of life measurements were examined. Investigators found that patients who had strokes reported significantly lower quality of life scores than those who had MI or cranial nerve palsy. After one year, however, these measurements did not show any significant difference. [62,64]The improved outcomes found in the CREST trial may reflect the increased experience of vascular surgeons with endovascular procedures and stent placement as well as the improvement in stents and device designs. This data supports that CAS is not inferior to CEA and both procedures can be safely offered to patients for the treatment of carotid artery disease.

**References**

[1] Roger, VL, Go AS, Lloyd-Jones DM et al. "Heart disease and stroke statistics-2012 up‐ date: a report from the American Heart Association." Circulation 125.1 (2012): E2-220.

Evaluation and Treatment of Carotid Artery Stenosis

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[2] Rockman C, Hoang H, Guo Y, et al. "The prevalence of carotid artery stenosis varies

[3] Mathieson E, Joakkimsen O, Bonaa K, et al. "Prevalence of and risk factors associated with carotid artery stenosis: the Troms Study." Cerebrovasc Dis 12 (2001): 44-51. [4] Sangiorgi G, Roversi S, Zoccai G, et al. "Sex-related differences in carotid plaque fea‐

[5] Kardys I, Vliegenthart R, Oudkerk M, et al. "The female advantage in cardiovascular diseae: do vascular beds contribute equally?" Am J Epidemiol 166 (2007): 403-412. [6] Agrinier N, Cournot M, Dallongeville J, et al. "Menopause and modifiable coronary heart disease risk factors: a population based study.." Maturitas 65 (2010): 237-243. [7] Wolf P, D'Agostino R, Belanger A, et al. "Probability of Stroke: A risk profile from the

[8] Wardlaw J, Chappell F, Best J, et al. "Non-invasive imaging compared with intra-ar‐ terial angiography in the diagnosis of symptomatic carotid stenosis: a meta-analysis."

[9] Jahromi A, Cina C, Liu Y, et al. "Sensitivity and specificity of color duplex ultrasound measurements in the estimation of the interval carotid artery stenosis: a systemic re‐

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Current overall recommendations by the Society of Vascular Surgery for intervention in patients with carotid artery disease are:

	- **a.** Asymptomatic patients >60% stenosis should be considered for CEA if that have a 3-5 year life expectancy and perioperative stroke/death rates are <3%
	- **b.** In patients with symptomatic stenosis >50% CEA is preferred, especially if patient is >70, has a long lesion (>15mm), preocclusive stenosis, lipid-rich plaque that can be completely removed, and have not had previous neck operations or radiation
	- **a.** Patient has a tracheal stoma, scarred and fibrotic tissue from previous ipsilateral surgery or radiation, prior cranial nerve injury, and lesions that extend proximal to the clavicle or distal to the C2 vertebral body
	- **b.** Patient has severe uncorrectable CAD, CHF or COPD
	- **a.** Insufficient data to recommend CAS for asymptomatic patients that are normal or high risk for CEA. [38]
